ToxSci Advance Access originally published online on September 14, 2005
Toxicological Sciences 2005 88(2):346-357; doi:10.1093/toxsci/kfi323
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Involvement of the Integrin-Linked Kinase Pathway in Hexachlorobenzene-Induced Gender-Specific Rat Hepatocarcinogenesis
INRS-Institut Armand-Frappier, Université du Québec, 245 Hymus Boulevard, Pointe-Claire, Québec, Canada, H9R 1G6
Received July 28, 2005; accepted September 9, 2005
Overexpression of the integrin-linked kinase (ILK) pathway disrupts cell-cell interactions, an epigenetic event leading to epithelial cell transformation. Female rats exposed to hexachlorobenzene (HCB) for 5 consecutive days and sampled 45 days later show a decrease in liver gap junctional intercellular communication. We hypothesized that HCB also alters E-cadherin expression and that this alteration is mediated by the ILK pathway. Hepatic ILK levels were markedly increased in HCB-treated female rats. Cytoplasmic/membrane levels of protein kinase B (Akt), a target of ILK, and its phosphorylated active form were decreased in treated female rats. Flow cytometric analysis showed a concomitant increase in nuclear Akt levels. Both ILK and Akt can phosphorylate glycogen synthetase kinase-3ß (GSK3ß), rendering it inactive. Phosphorylated-GSK3ß levels were higher in treated females and resulted in a twofold decrease in the activity of GSK3ß. The inactivation of GSK3ß in HCB-treated female rats resulted in the nuclear translocation of ß-catenin, as demonstrated by both immunocytochemistry and flow cytometric analyses. Western blot analysis showed an 84% decrease in E-cadherin levels in HCB-treated rats as compared to controls, and this decrease was not mediated by Snail activation. Mimicking the activation of ILK with specific GSK3ß inhibitors resulted in downregulation of E-cadherin levels but had no effect on Cx32 expression in the MH1C1 cells. Overall, these results indicate that hepatic E-cadherin is downregulated as a result of an overexpression of the ILK pathway. The concomitant HCB-induced downregulation of intercellular communication does not occur as a result of either E-cadherin downregulation or GSK3ß inactivation.
Key Words: Carcinogenesis; junction; E-cadherin; ß-catenin; glycogen synthetase kinase-3ß; connexins.
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